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1.  The Impact of Social Factors on Human Immunodeficiency Virus and Hepatitis C Virus Co-Infection in a Minority Region of Si-Chuan, the People's Republic of China: A Population-Based Survey and Testing Study 
PLoS ONE  2014;9(7):e101241.
While many human immunodeficiency virus (HIV) studies have been performed in Liangshan, most were focused only on HIV infection and based on a sampling survey. In order to fully understand HIV and hepatitis C virus (HCV) prevalence and related risk factors in this region, this study implemented in 2009, included a survey, physical examination, HIV and HCV test in two towns.
All residents in two towns of the Butuo county were provided a physical examination and blood tests for HIV and HCV, and then followed by an interview for questionnaire.
In total, 10,104 residents (92.4%) were enrolled and 9,179 blood samples were collected for HIV and HCV testing, 6,072 were from individuals >14 years old. The rates of HIV, HCV, and HIV/HCV co-infection were 11.4%, 14.0%, and 7.7%, respectively for >14-year-old residents. The 25–34 yr age group had the highest prevalence of HIV, HCV, and HIV/HCV co-infections, reaching 24.4%, 26.2% and 16.0%, respectively. Overall, males had a much higher prevalence of all infections than females (HIV: 16.3% vs. 6.8%, HCV: 24.6% vs. 3.9%, HIV/HCV co-infected: 14.7% vs. 1.1%, respectively; P = 0.000). Approximately half of intravenous drug users tested positive for HIV (48.7%) and 68.4% tested positive for HCV. Logistic regression analysis showed that five factors were significantly associated with HIV and HCV infection: gender (odds ratio [OR]  = 5.8), education (OR = 2.29); occupation (student as reference; farmer: OR = 5.02, migrant worker: OR = 6.12); drug abuse (OR = 18.0); and multiple sexual partners (OR = 2.92). Knowledge of HIV was not associated with infection.
HIV and HCV prevalence in the Liangshan region is very serious and drug use, multiple sexual partners, and low education levels were the three main risk factors. The government should focus on improving education and personal health awareness while enhancing drug control programs.
PMCID: PMC4079678  PMID: 24988219
2.  Increased In Situ Intestinal Absorption of Phytoestrogenic Diarylheptanoids from Curcuma comosa in Nanoemulsions 
AAPS PharmSciTech  2013;14(3):1055-1062.
Curcuma comosa has long been used as a gynecological medicine. Several diarylheptanoids have been purified from this plant, and their pharmacological effects were proven. However, there is no information about the absorption of C. comosa components to support the formulation usage. In the present study, C. comosa hexane extract and the mixture of its two major compounds, (4E,6E)-1,7-diphenylhepta-4,6-dien-3-ol (DA1) and (6E)-1,7-diphenylhept-6-en-3-ol (DA2), were formulated into nanoemulsions. The physical properties of the nanoemulsions and the in situ intestinal absorptions of DA1 and DA2 were evaluated. The results demonstrated the mean particle sizes at 0.207 ± 0.001 and 0.408 ± 0.014 μm, and the zeta potential at −14.57 ± 0.85 and −10.47 ± 0.32 mV for C. comosa nanoemulsion (C.c-Nano) and mixture of diarlylheptanoid nanoemulsions (DA-Nano), respectively. The entrapments of DA1 and DA2 were 76.61% and 75.41%, and 71.91% and 71.63% for C.c-Nano and DA-Nano, respectively. The drug loading ratios of DA1 and DA2 were 351.47 and 614.53 μg/mg, and 59.48 and 126.72 μg/mg for C.c-Nano and DA-Nano. The intestinal absorption rates of DA1 and DA2 were 0.329 ± 0.015 and 0.519 ± 0.026 μg/min/cm2 in C.c-Nano, and 0.380 ± 0.006 and 0.428 ± 0.036 μg/min/cm2 in DA-Nano, which were five to ten times faster than those in oil. In conclusion, the formulation in nanoemulsion forms obviously increased the intestinal absorption rate of diarylheptanoids.
PMCID: PMC3755175  PMID: 23797305
Curcuma comosa; diarylheptanoids; intestinal absorption; nanoemulsion; phytoestrogen
3.  Down-Regulation of TRPM8 in Pulmonary Arteries of Pulmonary Hypertensive Rats 
Pulmonary hypertension (PH) is characterized by profound vascular remodeling and alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Multiple transient receptor potential melastatin-related (TRPM) subtypes have been identified in vascular tissue. However, the changes in the expression and function of TRPM channels in pulmonary hypertension have not been characterized in detail.
We examined the expression of TRPM channels and characterized the functions of the altered TRPM channels in two widely used rat models of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH.
CH-exposed and MCT-treated rats developed severe PH and right ventricular hypertrophy, with a significant decrease in TRPM8 mRNA and protein expression in pulmonary arteries (PAs). The downregulation of TRPM8 was associated with significant reduction in menthol-induced cation-influx. Time-profiles showed that TRPM8 down-regulation occurred prior to the increase of right ventricular systolic pressure (RVSP) and right ventricular mass index (RVMI) in CH-exposed rats, but these changes were delayed in MCT–treated rats. The TRPM8 agonist menthol induced vasorelaxation in phenylephrine-precontracted PAs, and the vasorelaxing effects were significantly attenuated in PAs of both PH rat models, consistent with decreased TRPM8 expression.
Downregulation of TRPM8 may contribute to the enhanced vasoreactivity in PH.
PMCID: PMC4034698  PMID: 23817166
Transient receptor potential melastatin; Pulmonary hypertension; Calcium signaling; Monocrotaline; Chronic hypoxia; Menthol
4.  Projecting dynamic trends for HIV/AIDS in a highly endemic area of China: Estimation models for Liangshan Prefecture, Sichuan Province 
Current HIV research  2009;7(4):390-397.
This study describes the current situation and projects dynamic trends for HIV prevalence in a highly endemic area of China, Liangshan Prefecture, Sichuan Province. Epidemiological, behavioral, and population census data from multiple sources were analyzed to extract input for an Asian Epidemic Model (AEM). Fitting curves to historical trends in HIV prevalence were used as a baseline, and future intervention scenarios were explored using the AEM. For 2007, modeled data suggested ≈0.5% adult HIV prevalence in Liangshan, with an estimated 17,450 people living with HIV/AIDS and 3,400 new infections. With current high risk behaviors, the model predicts that adult prevalence will rise to 1.5% by 2020. Increased condom use and clean needle exchange among injection drug users (IDUs) have slowed the epidemic. The source of new HIV infections will change from a preponderance of IDU-related infections in 2007 (65.9%) to a mixed epidemic in 2020 (general population heterosexuals 45.2%, IDU 38.6%, homosexual transmission between men 12.7%, female sex workers and their clients 3.5%). We anticipate rising prevalence, stable incidence, and higher representation of sexual transmission over time. Prevention investments should target specific interventions toward sub-groups at highest risk, given that both IDUs and men who have sex with men will likely represent a majority of cases and serve as a bridge population.
PMCID: PMC4048065  PMID: 19601774
HIV; Asian Epidemic Model; epidemiologic modeling; substance abuse; homosexuality; China
5.  Novel SNP array analysis and exome sequencing detect a homozygous exon 7 deletion of MEGF10 causing early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) 
Neuromuscular disorders : NMD  2013;23(6):483-488.
Early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) is a myopathic disorder associated with mutations in MEGF10. By novel analysis of SNP array hybridization and exome sequence coverage, we diagnosed a 10-year old girl with EMARDD following identification of a novel homozygous deletion of exon 7 in MEGF10. In contrast to previously reported EMARDD patients, her weakness was more prominent proximally than distally, and involved her legs more than her arms. MRI of her pelvis and thighs showed muscle atrophy and fatty replacement. Ultrasound of several muscle groups revealed dense homogenous increases in echogenicity. Cloning and sequencing of the deletion breakpoint identified features suggesting the mutation arose by fork stalling and template switching. These findings constitute the first genomic deletion causing EMARDD, expand the clinical phenotype, and provide new insight into the pattern and histology of its muscular pathology.
PMCID: PMC3940074  PMID: 23453856
EMARDD; MEGF10; SNP array; exome sequencing; deletion analysis; myopathy
6.  A Novel Newborn Rat Kernicterus Model Created by Injecting a Bilirubin Solution into the Cisterna Magna 
PLoS ONE  2014;9(5):e96171.
Kernicterus still occurs around the world; however, the mechanism of bilirubin neurotoxicity remains unclear, and effective treatment strategies are lacking. To solve these problems, several kernicterus (or acute bilirubin encephalopathy) animal models have been established, but these models are difficult and expensive. Therefore, the present study was performed to establish a novel kernicterus model that is simple and affordable by injecting unconjugated bilirubin solution into the cisterna magna (CM) of ordinary newborn Sprague-Dawley (SD) rats.
On postnatal day 5, SD rat pups were randomly divided into bilirubin and control groups. Then, either bilirubin solution or ddH2O (pH = 8.5) was injected into the CM at 10 µg/g (bodyweight). For model characterization, neurobehavioral outcomes were observed, mortality was calculated, and bodyweight was recorded after bilirubin injection and weaning. Apoptosis in the hippocampus was detected by H&E staining, TUNEL, flow cytometry and Western blotting. When the rats were 28 days old, learning and memory ability were evaluated using the Morris water maze test.
The bilirubin-treated rats showed apparently abnormal neurological manifestations, such as clenched fists, opisthotonos and torsion spasms. Bodyweight gain in the bilirubin-treated rats was significantly lower than that in the controls (P<0.001). The early and late mortality of the bilirubin-treated rats were both dramatically higher than those of the controls (P = 0.004 and 0.017, respectively). Apoptosis and necrosis in the hippocampal nerve cells in the bilirubin-treated rats were observed. The bilirubin-treated rats performed worse than the controls on the Morris water maze test.
By injecting bilirubin into the CM, we successfully created a new kernicterus model using ordinary SD rats; the model mimics both the acute clinical manifestations and the chronic sequelae. In particular, CM injection is easy to perform; thus, more stable models for follow-up study are available.
PMCID: PMC4010446  PMID: 24796550
7.  Primary atypical teratoid/rhabdoid tumor of central nervous system in children: a clinicopathological analysis and review of literature in China 
Atypical teratoid/rhabdoid tumor (AT/RT) is a very rare and highly malignant embryonal tumor in the central nervous system (CNS). Five patients (4 girls and 1 boy) with AT/RT were treated in our hospital. The clinical histories, symptoms, neuroimaging aspects, therapies, histological and immunohistochemical findings and follow-up information were reviewed. The patients ranged from 8 to 40 months with a mean age of 20.6 months. One tumor was located in the spinal cord, two in cerebellum and two in the pineal region. The imagings of the tumors resemble medulloblastomas. Pathological examinations showed that one patient had medulloblastoma differentiation, one had choroid plexus carcinoma differentiation, and one had mesenchymal components. Immunohistochemical staining showed that all of the tumors lost the nuclear expression of integrase interactor 1 (INI1), and were positive for Vimentin, S-100 protein and epithelial membrane antigen. One case with no recurrence after 24 months may have benefited from radical excision and postoperative radiotherapy. The other 4 patients died 8, 4, 1 and 1-month respectively after operation without radiotherapy. The diagnosis of AT/RT depends on full sampling, careful observation the morphological characteristics and INI1 examination, even when the tumor are presented in uncommon sites, such as the spinal cord and the pineal region.
PMCID: PMC4069879  PMID: 24966951
Atypical teratoid/rhabdoid tumor; integrase interactor 1; spinal cord; pineal gland; cerebellum
8.  Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells 
Biochemical pharmacology  2013;85(7):10.1016/j.bcp.2013.01.023.
Fenretinide is significantly more effective in inducing apoptosis in cancer cells than all-trans retinoic acid (ATRA). The current study uses a genome-wide approach to understand the differential role fenretinide and ATRA have in inducing apoptosis in Huh7 cells. Fenretinide and ATRA-induced gene expressions and DNA bindings were profiled using microarray and chromatin immunoprecipitation with anti-RXRα antibody. The data showed that fenretinide was not a strong transcription regulator. Fenretinide only changed the expressions of 1 093 genes, approximately three times less than the number of genes regulated by ATRA (2 811). Biological function annotation demonstrated that both fenretinide and ATRA participated in pathways that determine cell fate and metabolic processes. However, fenretinide specifically induced Fas/TNFα-mediated apoptosis by increasing the expression of pro-apoptotic genes i.e., DEDD2, CASP8, CASP4, and HSPA1A/B; whereas, ATRA induced the expression of BIRC3 and TNFAIP3, which inhibit apoptosis by interacting with TRAF2. In addition, fenretinide inhibited the expression of the genes involved in RAS/RAF/ERK-mediated survival pathway. In contrast, ATRA increased the expression of SOSC2, BRAF, MEK, and ERK genes. Most genes regulated by fenretinide and ATRA were bound by RXRα, suggesting a direct effect. This study revealed that by regulating fewer genes, the effects of fenretinide become more specific and thus has fewer side effects than ATRA. The data also suggested that fenretinide induces apoptosis via death receptor effector and by inhibiting the RAS/RAF/ERK pathway. It provides insight on how retinoid efficacy can be improved and how side effects in cancer therapy can be reduced.
PMCID: PMC3857153  PMID: 23396089
retinoic acid receptor; retinoid x receptor; nuclear receptor; hepatocellular carcinoma; ChIP-Seq
10.  Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications 
The programmed cell death-1 receptor/programmed cell death-1 ligand (PD-1/PD-L1) pathway plays a crucial role in tumor evasion from host immunity. This study was designed to evaluate the association between circulating PD-L1 expression and prognosis in patients with advanced gastric cancer.
Totally 80 advanced gastric cancer patients and 40 health controls from Beijing Cancer Hospital were enrolled in the present study. Circulating PD-L1 expression was tested by enzyme-linked immunosorbent assay (ELISA). The associations between the expression level of PD-L1 and clinicopathological features and prognosis were analyzed statistically.
Expression of PD-L1 in advanced gastric cancer patients was significantly up-regulated compared with health people (P=0.006). The expression of PD-L1 was significantly correlated with differentiation and lymph node metastasis (P=0.026 and P=0.041, respectively). Although we didn’t find significant difference in all advanced gastric cancer patients with different PD-L1 expression, the adenocarcinoma patients with higher up-regulated PD-L1 expression had much better prognosis than low expression patients (65.6% vs. 44.7%, P=0.028).
PD-L1 was elevated in advance gastric cancer patients and may play an important role in tumor immune evasion and patients prognosis.
PMCID: PMC3937742  PMID: 24653632
Programmed cell death-1 ligands (PD-L1); tumor immunity; advanced gastric cancer; enzyme-linked immunosorbent assay (ELISA)
11.  A Robot-Assisted Surgical System Using a Force-Image Control Method for Pedicle Screw Insertion 
PLoS ONE  2014;9(1):e86346.
To introduce a robot-assisted surgical system for spinal posterior fixation that can automatically recognize the drilling state and stop potential cortical penetration with force and image information and to further evaluate the accuracy and safety of the robot for sheep vertebra pedicle screw placement.
The Robotic Spinal Surgery System (RSSS) was composed of an optical tracking system, a navigation and planning system, and a surgical robot equipped with a 6-DOF force/torque sensor. The robot used the image message and force signals to sense the different operation states and to prevent potential cortical penetration in the pedicle screw insertion operation. To evaluate the accuracy and safety of the RSSS, 32 screw insertions were conducted. Furthermore, six trajectories were deliberately planned incorrectly to explore whether the robot could recognize the different drilling states and immediately prevent cortical penetration.
All 32 pedicle screws were placed in the pedicle without any broken pedicle walls. Compared with the preoperative planning, the average deviations of the entry points in the axial and sagittal views were 0.50±0.33 and 0.65±0.40 mm, and the average deviations of the angles in the axial and sagittal views were 1.9±0.82° and 1.48±1.2°. The robot successfully recognized the different drilling states and prevented potential cortical penetration. In the deliberately incorrectly planned trajectory experiments, the robot successfully prevented the cortical penetration.
These results verified the RSSS’s accuracy and safety, which supported its potential use for the spinal surgery.
PMCID: PMC3899254  PMID: 24466043
12.  OmicCircos: A Simple-to-Use R Package for the Circular Visualization of Multidimensional Omics Data 
Cancer Informatics  2014;13:13-20.
OmicCircos is an R software package used to generate high-quality circular plots for visualizing genomic variations, including mutation patterns, copy number variations (CNVs), expression patterns, and methylation patterns. Such variations can be displayed as scatterplot, line, or text-label figures. Relationships among genomic features in different chromosome positions can be represented in the forms of polygons or curves. Utilizing the statistical and graphic functions in an R/Bioconductor environment, OmicCircos performs statistical analyses and displays results using cluster, boxplot, histogram, and heatmap formats. In addition, OmicCircos offers a number of unique capabilities, including independent track drawing for easy modification and integration, zoom functions, link-polygons, and position-independent heatmaps supporting detailed visualization.
OmicCircos is available through Bioconductor at An extensive vignette in the package describes installation, data formatting, and workflow procedures. The software is open source under the Artistic–2.0 license.
PMCID: PMC3921174  PMID: 24526832
R package; circular plot; genomic variation
13.  Adding an unnatural covalent bond to proteins through proximity-enhanced bioreactivity 
Nature methods  2013;10(9):10.1038/nmeth.2595.
Natural proteins often rely on the disulfide bond to covalently link side chains. Here we genetically introduce a new type of covalent bond into proteins by enabling an unnatural amino acid to react with a proximal cysteine. We demonstrate the utility of this bond for enabling irreversible binding between an affibody and its protein substrate, capturing peptide-protein interactions in mammalian cells, and improving the photon output of fluorescent proteins.
PMCID: PMC3882359  PMID: 23913257
14.  A cross-sectional study of the clinical characteristics of hospitalized children with community-acquired pneumonia in eight eastern cities in China 
Community-acquired pneumonia in children is common in China. To understand current clinical characteristics and practice, we conducted a cross-sectional study to analyze quality of care on childhood pneumonia in eight eastern cities in China.
Consecutive hospital records between January 1, 2010 and December 31, 2010 were collected from 13 traditional Chinese medicine (TCM) and western medicine (WM) hospitals in February, May, August, and November (25 cases per season, 100 cases over the year), respectively. A predesigned case report form was used to extract data from the hospital medical records.
A total of 1298 cases were collected and analyzed. Symptoms and signs upon admission at TCM and WM hospitals were cough (99.3% vs. 98.6%), rales (84.8% vs. 75.0%), phlegm (83.3% vs. 49.1%), and fever (74.9% vs. 84.0%) in frequency. Patients admitted to WM hospitals had symptoms and signs for a longer period prior to admission than patients admitted to TCM hospitals. Testing to identify etiologic agents was performed in 1140 cases (88.4%). Intravenous antibiotics were administered in 99.3% (595/598) of cases in TCM hospitals and in 98.6% (699/700) of cases in WM hospitals. Besides, Chinese herbal extract injection was used more frequently in TCM hospitals (491 cases, 82.1%) than in WM hospitals (212 cases, 30.3%) (p < 0.01). At discharge, 818 cases (63.0%) were clinically cured, with a significant difference between the cure rates in TCM (87.6%) and WM hospitals (42.0%) (OR = 9.8, 95% confidence interval (CI): 7.3 ~ 12.9, p < 0.01). Pathogen and previous medical history were more likely associated with the disappearance of rales (OR = 7.2, 95% CI: 4.8 ~ 10.9). Adverse effects were not reported from the medical records.
Intravenous use of antibiotics is highly prevalent in children with community-acquired pneumonia regardless of aetiology. There was difference between TCM and WM hospitals with regard to symptom profile and the use of antibiotics. Intravenous use of herbal injection was higher in TCM hospitals than in WM hospitals. Most of the cases were diagnosed based on clinical signs and symptoms without sufficient confirmation of aetiology. Audit of current practice is urgently needed to improve care.
PMCID: PMC3880031  PMID: 24364897
Childhood pneumonia; Community-acquired; Clinical characteristics; Treatment; Cross-sectional study; Chinese population
15.  Phosphatase of regenerating liver-3 (PRL-3) is associated with metastasis and poor prognosis in gastric carcinoma 
PRL-3 is a member of phosphatases of regenerating liver family, characterized by phosphatase active domain and C-terminal prenylation motif. Overexpression of PRL-3 has been implicated in multiple cancers. Here we examined the clinical significance of PRL-3 in gastric cancer together with its metastatic biological functions utilizing different structural mutants.
PRL-3 expression was analyzed immunohistochemically in 196 gastric cancer patients and 21 cases of liver metastasis. A series of wild type PRL-3 or its mutant plasmids were expressed in BGC823 cells to investigate the relationship between its catalytic activity, cellular localization and metastatic potential in vitro.
Positive staining of PRL-3 was observed in 19.4% (38/196) gastric cancer tissues compared with 76.2% (16/21) in liver metastasis. Statistical analysis revealed that PRL-3 expression correlated with lymph node metastasis and vascular invasion (P < 0.05). Patients with high PRL-3 expression showed poorer 5-year overall survival (P = 0.011). Wild type PRL-3 expressing cells resulted in enhanced migration and invasion ability, which were greatly crippled in form of PRL-3(C104S) or PRL-3(ΔCAAX) mutants accompanied with its alteration in subcellular localization.
Metastasis associated protein PRL-3 may serve as a potential prognostic biomarker in human gastric cancer. Both the phosphatase catalytic activity and cellular localization are critical for its function.
PMCID: PMC3878674  PMID: 24330843
PRL-3; Gastric cancer; Prognosis; Metastasis
16.  His26 Protonation in Cytochrome c Triggers Microsecond β-sheet Formation and Heme Exposure: Implications for Apoptosis 
Journal of the American Chemical Society  2012;134(46):19061-19069.
Cytochrome c unfolds locally and reversibly upon heating at pH 3. UV resonance Raman (UVRR) spectra reveal that instead of producing unordered structure, unfolding converts turns and some helical elements to β-sheet. It also disrupts the Met80-heme bond, and was earlier shown to induce peroxidase activity. Aromatic residues that are H-bonded to a heme propionate (Trp59 and Tyr48) alter their orientation, indicating heme displacement. T-jump/UVRR measurements give time constants of 0.2, 3.9 and 67 µs for successive phases of β-sheet formation and concomitant reorientation of Trp59. UVRR spectra reveal protonation of histidines, and specifically of His26, whose H-bond to Pro44 anchors the 40s Ω loop; this loop is known to be the least stable ‘foldon’ in the protein. His26 protonation is proposed to disrupt its H-bond with Pro44, triggering the extension of a short β-sheet segment at the ‘neck’ of the 40s Ω loop into the loop itself and back into the 60’s and 70’s helices. The secondary structure change displaces the heme via H-bonds from residues in the growing β-sheet, thereby exposing it to exogenous ligands, and inducing peroxidase activity. This unfolding mechanism may play a role in cardiolipin peroxidation by cyt c during apoptosis.
PMCID: PMC3529097  PMID: 23094892
17.  DNA Translocation through Hydrophilic Nanopore in Hexagonal Boron Nitride 
Scientific Reports  2013;3:3287.
Ultra-thin solid-state nanopore with good wetting property is strongly desired to achieve high spatial resolution for DNA sequencing applications. Atomic thick hexagonal boron nitride (h-BN) layer provides a promising two-dimensional material for fabricating solid-state nanopores. Due to its good oxidation resistance, the hydrophilicity of h-BN nanopore device can be significantly improved by UV-Ozone treatment. The contact angle of a KCl-TE droplet on h-BN layer can be reduced from 57° to 26° after the treatment. Abundant DNA translocation events have been observed in such devices, and strong DNA-nanopore interaction has been revealed in pores smaller than 10 nm in diameter. The 1/f noise level is closely related to the area of suspended h-BN layer, and it is significantly reduced in smaller supporting window. The demonstrated performance in h-BN nanopore paves the way towards base discrimination in a single DNA molecule.
PMCID: PMC3836030  PMID: 24256703
18.  Bone marrow mesenchymal stem cells protect against retinal ganglion cell loss in aged rats with glaucoma 
Glaucoma is a common eye disease in the aged population and has severe consequences. The present study examined the therapeutic effects of bone marrow mesenchymal stem cell (BMSC) transplantation in preventing loss of visual function in aged rats with glaucoma caused by laser-induced ocular hypertension. We found that BMSCs promoted survival of retinal ganglion cells in the transplanted eye as compared with the control eye. Further, in swimming tests guided by visual cues, the rats with a BMSC transplant performed significantly better. We believe that BMSC transplantation therapy is effective in treating aged rats with glaucoma.
PMCID: PMC3817004  PMID: 24204132
glaucoma; stem cell; transplantation; cell therapy; aging
19.  Genetic Background May Contribute to PAM50 Gene Expression Breast Cancer Subtype Assignments 
PLoS ONE  2013;8(8):e72287.
Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of “snapshot” expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.
PMCID: PMC3756056  PMID: 24015230
20.  Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia 
Cancer cell  2012;22(2):153-166.
Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL, and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2 negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.
PMCID: PMC3422513  PMID: 22897847
21.  A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia 
PLoS ONE  2013;8(8):e73576.
Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. CMD can be inherited in an autosomal dominant (AD) trait or occur after de novo mutations in the pyrophosphate transporter ANKH. Although the autosomal recessive (AR) form of CMD had been mapped to 6q21-22 the mutation has been elusive. In this study, we performed whole-exome sequencing for one subject with AR CMD and identified a novel missense mutation (c.716G>A, p.Arg239Gln) in the C-terminus of the gap junction protein alpha-1 (GJA1) coding for connexin 43 (Cx43). We confirmed this mutation in 6 individuals from 3 additional families. The homozygous mutation cosegregated only with affected family members. Connexin 43 is a major component of gap junctions in osteoblasts, osteocytes, osteoclasts and chondrocytes. Gap junctions are responsible for the diffusion of low molecular weight molecules between cells. Mutations in Cx43 cause several dominant and recessive disorders involving developmental abnormalities of bone such as dominant and recessive oculodentodigital dysplasia (ODDD; MIM #164200, 257850) and isolated syndactyly type III (MIM #186100), the characteristic digital anomaly in ODDD. However, characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with the recessive Arg239Gln Cx43 mutation. Bone remodeling mechanisms disrupted by this novel Cx43 mutation remain to be elucidated.
PMCID: PMC3741164  PMID: 23951358
22.  Multi-SNP Analysis of GWAS Data Identifies Pathways Associated with Nonalcoholic Fatty Liver Disease 
PLoS ONE  2013;8(7):e65982.
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease; the histological spectrum of which ranges from steatosis to steatohepatitis. Nonalcoholic steatohepatitis (NASH) often leads to cirrhosis and development of hepatocellular carcinoma. To better understand pathogenesis of NAFLD, we performed the pathway of distinction analysis (PoDA) on a genome-wide association study dataset of 250 non-Hispanic white female adult patients with NAFLD, who were enrolled in the NASH Clinical Research Network (CRN) Database Study, to investigate whether biologic process variation measured through genomic variation of genes within these pathways was related to the development of steatohepatitis or cirrhosis. Pathways such as Recycling of eIF2:GDP, biosynthesis of steroids, Terpenoid biosynthesis and Cholesterol biosynthesis were found to be significantly associated with NASH. SNP variants in Terpenoid synthesis, Cholesterol biosynthesis and biosynthesis of steroids were associated with lobular inflammation and cytologic ballooning while those in Terpenoid synthesis were also associated with fibrosis and cirrhosis. These were also related to the NAFLD activity score (NAS) which is derived from the histological severity of steatosis, inflammation and ballooning degeneration. Eukaryotic protein translation and recycling of eIF2:GDP related SNP variants were associated with ballooning, steatohepatitis and cirrhosis. Il2 signaling events mediated by PI3K, Mitotic metaphase/anaphase transition, and Prostanoid ligand receptors were also significantly associated with cirrhosis. Taken together, the results provide evidence for additional ways, beyond the effects of single SNPs, by which genetic factors might contribute to the susceptibility to develop a particular phenotype of NAFLD and then progress to cirrhosis. Further studies are warranted to explain potential important genetic roles of these biological processes in NAFLD.
PMCID: PMC3716806  PMID: 23894275
23.  Cross-Sectional Surveys of Measles Antibodies in the Jiangsu Province of China from 2008 to 2010: The Effect of High Coverage with Two Doses of Measles Vaccine among Children 
PLoS ONE  2013;8(6):e66771.
Changes in the epidemiological characteristics of measles since 2007 appeared in the Jiangsu province. Although the reported coverage with two doses of measles vaccine was greater than 95% in most regions of the province, measles incidence remained high across the whole province. Cross-sectional serological surveys of measles antibodies in the Jiangsu province of China were conducted from 2008 to 2010 to assess and track population immunity.
Measles-specific IgG levels were measured in serum samples using ELISA. GMTs and seroprevalence with 95% CIs were calculated by region, gender, and age. ANOVA and χ2 tests were used to test for statistically significant differences between groups for GMT levels and seroprevalence, respectively.
Seroprevalence showed a significantly increasing trend annually (CMH χ2 = 40.32, p<0.0001). Although the seroprevalence among children aged 2–15 years was consistently over 95%, vaccine-induced measles antibodies may wane over time. Measles seropositivity in the Jiangsu province was 91.7% (95% CI: 90.1–93.2%) in 2010. Among adults aged 15 to 29-year-olds, the seropositivity rate was 88.4% (95% CI: 82.7–92.8%).
Vaccination strategies may need to be adjusted depending on the individual age and regions, particularly individuals between the ages of 8 months-14 years old and 20–29 years old. Additional SIAs are likely required to eliminate measles in China.
PMCID: PMC3692513  PMID: 23825562
24.  PPARβ Regulates Liver Regeneration by Modulating Akt and E2f Signaling 
PLoS ONE  2013;8(6):e65644.
The current study tests the hypothesis that peroxisome proliferator-activated receptor β (PPARβ) has a role in liver regeneration due to its effect in regulating energy homeostasis and cell proliferation. The role of PPARβ in liver regeneration was studied using two-third partial hepatectomy (PH) in Wild-type (WT) and PPARβ-null (KO) mice. In KO mice, liver regeneration was delayed and the number of Ki-67 positive cells reached the peak at 60 hr rather than at 36–48 hr after PH shown in WT mice. RNA-sequencing uncovered 1344 transcriptomes that were differentially expressed in regenerating WT and KO livers. About 70% of those differentially expressed genes involved in glycolysis and fatty acid synthesis pathways failed to induce during liver regeneration due to PPARβ deficiency. The delayed liver regeneration in KO mice was accompanied by lack of activation of phosphoinositide-dependent kinase 1 (PDK1)/Akt. In addition, cell proliferation-associated increase of genes encoding E2f transcription factor (E2f) 1–2 and E2f7–8 as well as their downstream target genes were not noted in KO livers 36–48 hr after PH. E2fs have dual roles in regulating metabolism and proliferation. Moreover, transient steatosis was only found in WT, but not in KO mice 36 hr after PH. These data suggested that PPARβ-regulated PDK1/Akt and E2f signaling that controls metabolism and proliferation is involved in the normal progression of liver regeneration.
PMCID: PMC3688817  PMID: 23823620
25.  Combination of Selenium and Green Tea Improves the Efficacy of Chemoprevention in a Rat Colorectal Cancer Model by Modulating Genetic and Epigenetic Biomarkers 
PLoS ONE  2013;8(5):e64362.
Dietary supplementation of selenium and green tea holds promise in cancer prevention. In this study, we evaluated the efficacies of selenium and green tea administered individually and in combination against colorectal cancer in an azoxymethane (AOM)-induced rat colonic carcinogenesis model and determined the underlying mechanisms of the protection. Four-week old Sprague-Dawley male rats were fed with diets containing 0.5% green tea extract, 1ppm selenium as selenium-enriched milk protein, or combination of 1ppm selenium and 0.5% green tea extract. Animals received 2 AOM (15 mg/kg) treatments to induce colonic oncogenesis. Rats were killed 8 or 30 wk later after the last AOM to examine the effect of dietary intervention on aberrant crypt foci (ACF) formation or tumor development. On sacrifice, colons were examined for ACF and tumors, the mRNA levels of SFRP5 and Cyclin D1, and the proteins levels of ß-catenin, COX-2, Ki-67, DNMT1 and acetyl histone H3. The combination of selenium and green tea resulted in a significant additive inhibition of large ACF formation, this effect was greater than either selenium or green tea alone, P<0.01; the combination also had a significant additive inhibition effect on all tumor endpoints, the effect of the combination diet on tumor incidence, multiplicity and size was greater than selenium or green tea alone, P<0.01. Rats fed the combination diet showed marked reduction of DNMT1 expression and induction of histone H3 acetylation, which were accompanied by restoration of SFRP5 mRNA in normal-appearing colonic crypts. The combination diet also significantly reduced ß-catenin nuclear translocation, Cyclin D1 expression and cell proliferation. These data show, for the first time, that combination of selenium and green tea is more effective in suppressing colorectal oncogenesis than either agent alone. The preventive effect is associated with regulation of genetic and epigenetic biomarkers implicated in colonic carcinogenesis.
PMCID: PMC3662759  PMID: 23717604

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